How DNA Loops Help Distant Enhancers Control Genes

Some enhancers are located near the genes they control, or within the genes themselves. Others, known as distal enhancers, may be millions of nucleotides away, with many other genes in between.

How Do Distant Enhancers Reach the Genes They Regulate?

The existence of distal enhancers “seems ridiculous,” says Bickmore. “How do you get that information from there to here and to the genes that need to be activated? That’s a question that remains largely unanswered.”

One answer comes in the form of a loop.

Rather than traveling along the DNA in a straight line, distal enhancers can be brought into close proximity with the genes they regulate through a great loop of DNA. More precisely, these loops form in chromatin—the combination of DNA and its packaging proteins.

The loops are created by a protein motor called cohesin. Cohesin moves along the DNA strand, pushing it out into a loop as it goes.

Chromatin Loops Create Fluid Transcriptional Hubs

What happens after cohesin forms a loop and brings an enhancer and a gene together? Scientists once thought the elements would stick together or aggregate into molecular machines. Instead, the components appear to form a loose but dense mass in which they interact weakly, briefly, and indiscriminately. This type of structure is sometimes called a condensate.

These transcriptional hubs are highly fluid and vary from cell to cell. “There’s going to be a little bit of loop extrusion going on here, and in the next cell it might be here, and the whole thing is spinning incredibly fast,” Bickmore said.

Even if two cells are conceptually identical, such as two skin cells, the activity of the gene-regulation machinery is never exactly the same in each cell at any given moment.

How Chromatin Structure Controls Gene Activity

Chromatin loops are just one reason gene transcription depends on the shape and structure of the surrounding chromatin.

Textbook image Chromosomes are the 46 units into which the human genome is divided. When a cell is not actively dividing, its chromatin unwinds from the compact X-shaped clusters seen during cell division and looks more like a tangled mass.

Even within that apparent chaos, however, there is order. Some chromatin is tightly packed into a form called heterochromatin. The DNA in heterochromatin is relatively inaccessible to transcription factors, so the genes it contains are usually silent.

Other regions are looser, more open, and more accessible. This form of chromatin is called euchromatin.